Alternative titles; symbols
HGNC Approved Gene Symbol: CD3E
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:118,304,730-118,316,173 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Immunodeficiency 18 | 615615 | Autosomal recessive | 3 |
| Immunodeficiency 18, SCID variant | 615615 | Autosomal recessive | 3 |
The T-cell antigen receptor is composed of multiple subunits: alpha (see 186880), beta (see 186930), gamma (186740), delta (186790), epsilon, and zeta (186780). The last 4 constitute T3. The first 2 are linked by disulfide bonds. The gamma and delta T3 membrane proteins are glycoproteins; T3-epsilon is not glycosylated. Gold et al. (1986) cloned cDNA corresponding to the T3-epsilon gene, T3E.
Clevers et al. (1988) reported the isolation and structural analysis of the CD3E gene. They found that the CD3E gene consists of 9 exons. Three exons, encoding the junction of the leader peptide and the mature protein, were small (21, 15, and 18 bp, respectively). The murine gene contained only 2 such miniexons, the sequences of which were not homologous to those of the 3 human miniexons. From comparison of intron sequences, however, the regions surrounding the human miniexons III and IV appear to be closely related to those surrounding murine miniexons III and IV.
In a series of experiments utilizing both somatic cell hybrids and chromosomal hybridization in situ, Gold et al. (1987) showed that both the delta and epsilon subunits are coded by 11q23. The ETS1 (164720) gene is also located in 11q23. Several genes, preferentially expressed in human cells of hematopoietic and neuroectodermal origins, map to human 11q23 and murine chromosome 9. Thus, in that area, there may be a gene cluster important in cell proliferation and differentiation. See THY1 (188230). See 186740 for a discussion of linkage to CD3D and CD3G.
Clevers et al. (1988) showed by pulsed-field electrophoresis that the CD3E gene is separated from the CD3G/CD3D gene pair by at least 30 kb but by no more than 300 kb. Because of evidence from studies in the nonobese diabetic (nod) mouse indicating that 1 diabetogenic gene maps to the mouse Thy1 locus, Wong et al. (1991) investigated loci in the homologous region in the human, 11q23. A RFLP analysis of the CD3E locus in 168 Caucasoid patients with type I diabetes showed a significant difference in the frequency of the CD3E 8-kb allele between male and female patients and between female patients and healthy female controls. They interpreted the results as suggesting that a gene on 11q23 may confer susceptibility to type I diabetes in women; see 125852.
Animals deficient in pre-TCR-alpha have few alpha-beta lineage cells but an increased number of gamma-delta T cells. These gamma-delta T cells exhibit more extensive TCR-beta rearrangement than gamma-delta T cells from wildtype mice. These observations are consistent with the idea that different signals emanating from the gamma-delta-TCR and pre-TCR instruct lineage commitment. Using confocal microscopy and biochemistry to analyze the initiation of signaling, Saint-Ruf et al. (2000) showed that the pre-TCR, but not the gamma-delta TCR, colocalizes with the p56(lck) Src kinase (153390) into glycolipid-enriched membrane domains (rafts) apparently without any need for ligation. This results in the phosphorylation of CD3-epsilon and ZAP70 (176947) signal transducing molecules. Saint-Ruf et al. (2000) stated that their results indicated clear differences between pre-TCR and gamma-delta-TCR signaling.
Belghith et al. (2003) reported that treatment with CD3E-specific antibodies induced transferable T-cell-mediated tolerance involving CD4+CD25+ cells. However, these CD4+CD25+ T cells were distinct from naturally occurring regulatory T cells that control physiologic autoreactivity. CD3E-specific antibody treatment induced remission in nonobese diabetic (NOD) Cd28 (186760)-null mice that were devoid of such regulatory cells. Remission of diabetes was abrogated by coadministration of a neutralizing TGF-beta (190180)-specific antibody. The central role of TGF-beta was further suggested by its increased, long-lasting production by CD4+ T cells from tolerant mice. Belghith et al. (2003) concluded that their data explained the intriguing tolerogenic effect of CD3-specific antibodies and positioned them as the first clinically applicable pharmacologic stimulant of TGF-beta-producing regulatory CD4+ T cells.
In a child with a mild form of primary immunodeficiency-18 (IMD18; 615615), originally reported by Le Deist et al. (1991), Soudais et al. (1993) identified compound heterozygous mutations in the CD3E gene (186830.0001-186830.0002).
In a child, born of consanguineous parents, with IMD18 manifesting as T cell-negative, B cell-positive, natural killer (NK) cell-positive severe combined immunodeficiency (SCID), De Saint Basile et al. (2004) identified a homozygous deletion mutation in the CD3E gene (186830.0003). Two sibs were similarly affected, and all 3 patients died in infancy.
DeJarnette et al. (1998) generated mice that lack the Cd3e gene yet retain normal expression of the closely linked Cd3g and Cd3d genes. These mice exhibited an early arrest in T-cell development. Moreover, the developmental defect could be rescued by expression of a Cd3e transgene. These results identified an essential role for CD3-epsilon in T-cell development not shared by the proteins encoded by CD3-gamma or CD3-delta.
In a 5-year-old boy with a mild form of immunodeficiency-18 (IMD18; 615615), originally reported by Le Deist et al. (1991) and Thoenes et al. (1992), Soudais et al. (1993) identified compound heterozygous mutations in the CD3E gene: a T-to-C transition in intron 7, inherited maternally, and a G-to-A transition in exon 6, resulting in a trp59-to-ter (W59X; 186830.0002) substitution, inherited paternally. Transcript analysis showed that the intronic mutation caused a deletion of exon 7, which encodes the transmembrane domain. Each unaffected parent was heterozygous for 1 of the mutations. Patient lymphocytes had decreased membrane expression of TCR/CD3. Thoenes et al. (1992) had shown that the CD3E mRNA was abnormally small and present at a reduced level in the patient's T cells. Soudais et al. (1993) showed that a small amount of normal-sized CD3E transcript of maternal origin was also expressed in the patient.
For discussion of the trp59-to-ter (W59X) mutation in the CD3E gene that was found in compound heterozygous state in a patient with immunodeficiency-18 (IMD18; 615615) by Soudais et al. (1993), see 186830.0001.
In a patient, born of consanguineous parents, with immunodeficiency-18 (IMD18; 615615) manifesting as T-, B+, NK+ SCID, de Saint Basile et al. (2004) identified a homozygous 2-bp deletion at nucleotide 128 in exon 5 of the CDE3 gene, resulting in a frameshift at codon 43 and a stop codon 13 residues downstream and predicting a truncation of the CD3E chain in its extracellular domain. This CD3E mutation was found in combination with a wildtype allele in DNA from the patient's father; DNA from her mother was not available for study. Two sibs were affected, and all 3 patients died in infancy.
Belghith, M., Bluestone, J. A., Barriot, S., Megret, J., Bach, J.-F., Chatenoud, L. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nature Med. 9: 1202-1208, 2003. [PubMed: 12937416] [Full Text: https://doi.org/10.1038/nm924]
Clevers, H. C., Dunlap, S., Wileman, T. E., Terhorst, C. Human CD3-epsilon gene contains three miniexons and is transcribed from a non-TATA promoter. Proc. Nat. Acad. Sci. 85: 8156-8160, 1988. [PubMed: 3267235] [Full Text: https://doi.org/10.1073/pnas.85.21.8156]
de Saint Basile, G., Geissmann, F., Flori, E., Uring-Lambert, B., Soudais, C., Cavazzana-Calvo, M., Durandy, A., Jabado, N., Fischer, A., Le Diest, F. Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3. J. Clin. Invest. 114: 1512-1517, 2004. [PubMed: 15546002] [Full Text: https://doi.org/10.1172/JCI22588]
DeJarnette, J. B., Sommers, C. L., Huang, K., Woodside, K. J., Emmons, R., Katz, K., Shores, E. W., Love, P. E. Specific requirement for CD3-epsilon in T cell development. Proc. Nat. Acad. Sci. 95: 14909-14914, 1998. [PubMed: 9843989] [Full Text: https://doi.org/10.1073/pnas.95.25.14909]
Gold, D. P., Puck, J. M., Pettey, C. L., Cho, M., Coligan, J., Woody, J. N., Terhorst, C. Isolation of cDNA clones encoding the 20K non-glycosylated polypeptide chain of the human T-cell receptor/T3 complex. Nature 321: 431-434, 1986. Note: Erratum: Nature 324: 702 only, 1986. [PubMed: 3012357] [Full Text: https://doi.org/10.1038/321431a0]
Gold, D. P., van Dongen, J. J. M., Morton, C. C., Bruns, G. A. P., van den Elsen, P., Geurts van Kessel, A. H. M., Terhorst, C. The gene encoding the epsilon subunit of the T3/T-cell receptor complex maps to chromosome 11 in humans and to chromosome 9 in mice. Proc. Nat. Acad. Sci. 84: 1664-1668, 1987. [PubMed: 2882512] [Full Text: https://doi.org/10.1073/pnas.84.6.1664]
Le Deist, F., Thoenes, G., Corado, J., Lisowska-Grospierre, B., Fischer, A. Immunodeficiency with low expression of the T cell receptor/CD3 complex: effect on T lymphocyte activation. Europ. J. Immun. 21: 1641-1647, 1991. [PubMed: 1676369] [Full Text: https://doi.org/10.1002/eji.1830210709]
Saint-Ruf, C., Panigada, M., Azogui, O., Debey, P., von Boehmer, H., Grassi, F. Different initiation of pre-TCR and gamma-delta-TCR signalling. Nature 406: 524-527, 2000. [PubMed: 10952314] [Full Text: https://doi.org/10.1038/35020093]
Soudais, C., de Villartay, J.-P., Le Deist, F., Fischer, A., Lisowska-Grospierre, B. Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency. Nature Genet. 3: 77-81, 1993. [PubMed: 8490660] [Full Text: https://doi.org/10.1038/ng0193-77]
Thoenes, G., Soudais, C., Le Deist, F., Griscelli, C., Fischer, A., Lisowska-Grospierre, B. Structural analysis of low TCR-CD3 complex expression in T cells of an immunodeficient patient. J. Biol. Chem. 267: 487-493, 1992. [PubMed: 1370449]
Wong, S., Moore, S., Orisio, S., Millward, A., Demaine, A. G. Susceptibility to type I diabetes in women is associated with the CD3 epsilon locus on chromosome 11. Clin. Exp. Immun. 83: 69-73, 1991. [PubMed: 1671006] [Full Text: https://doi.org/10.1111/j.1365-2249.1991.tb05590.x]